The Endocannabinoid System as an Emerging Target of Pharmacotherapy

Abstract

“The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. Such studies have been greatly facilitated by the introduction of selective cannabinoid receptor antagonists and inhibitors of endocannabinoid metabolism and transport, as well as mice deficient in cannabinoid receptors or the endocannabinoid-degrading enzyme fatty acid amidohydrolase. In the past decade, the endocannabinoid system has been implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and in peripheral organs. More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson’s and Huntington’s disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few. An impediment to the development of cannabinoid medications has been the socially unacceptable psychoactive properties of plant-derived or synthetic agonists, mediated by CB(1) receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB(1) receptor antagonist, such as in obesity, and may also be absent when the action of endocannabinoids is enhanced indirectly through blocking their metabolism or transport. The use of selective CB(2) receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoids may also be limited through the use of preparations with controlled composition and the careful selection of dose and route of administration. The growing number of preclinical studies and clinical trials with compounds that modulate the endocannabinoid system will probably result in novel therapeutic approaches in a number of diseases for which current treatments do not fully address the patients’ need. Here, we provide a comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy.”

Future Directions

“The length of this review, necessitated by the steady growth in the number of indications for the potential therapeutic use of cannabinoid-related medications, is a clear sign of the emerging importance of this field. This is further underlined by the quantity of articles in the public database dealing with the biology of cannabinoids, which numbered ∼200 to 300/year throughout the 1970s to reach an astonishing 5900 in 2004. The growing interest in the underlying science has been matched by a growth in the number of cannabinoid drugs in pharmaceutical development from two in 1995 to 27 in 2004, with the most actively pursued therapeutic targets being pain, obesity, and multiple sclerosis (Hensen, 2005). As in any rapidly growing area of research, not all the leads will turn out to be useful or even valid. Nevertheless, it is safe to predict that new therapeutic agents that affect the activity of the endocannaboinoid system will emerge and become members of our therapeutic armamentarium. The plant-derived cannabinoid preparation Sativex has already gained regulatory approval in Canada for the treatment of spasticity and pain associated with multiple sclerosis, and the CB1 receptor antagonist rimonabant has been approved in Europe and is awaiting Food and Drug Administration approval in the United States for the treatment of the metabolic syndrome. Undoubtedly, these will be followed by new and improved compounds aimed at the same or additional targets in the endocannabinoid system. However, it may be only after the widespread therapeutic use of such compounds that some important side effects will emerge. Although this occurrence would be undesirable from a health care perspective, such side effects may shed further light on the biological functions of endocannabinoids in health and disease.”

http://pharmrev.aspetjournals.org/content/58/3/389.long

Cannabinoid receptor type 1 and 2 expression in the skin of healthy dogs and dogs with atopic dermatitis

“Cannabinoid receptor type 1 and 2 expression in the skin of healthy dogs and dogs with atopic dermatitis…The endocannabinoid system and cannabimimetic compounds protect against effects of allergic inflammatory disorders in various species of mammals. Results of the present study contributed to knowledge of the endocannabinoid system and indicated this system may be a target for treatment of immune-mediated and inflammatory disorders such as allergic skin diseases in dogs.”

http://www.ncbi.nlm.nih.gov/pubmed/22738050

7-Oxo-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamides as Selective CB2 Cannabinoid Receptor Ligands: Structural Investigations around a Novel Class of Full Agonists

“Cannabinoid receptor agonists have gained attention as potential therapeutic targets of inflammatory and neuropathic pain. Here, we report the identification and optimization of a series of 7-oxo-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide derivatives as a novel chemotype of selective cannabinoid CB2 receptor agonists… 7-Oxo-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamides as Selective CB2 Cannabinoid Receptor Ligands: Structural Investigations around a Novel Class of Full Agonists.”

http://www.ncbi.nlm.nih.gov/pubmed/22738271

Modulation of inflammatory responses by a cannabinoid-2-selective agonist after spinal cord injury

“Modulation of inflammatory responses by a cannabinoid-2-selective agonist after spinal cord injury… These results demonstrate that the improvement in motor and autonomic function resulting from treatment with a selective CB2 agonist is associated with a significant effect on inflammatory responses in the spinal cord following injury.”

http://www.ncbi.nlm.nih.gov/pubmed/21970496

Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis

“Cannabis-based medicines have a number of therapeutic indications, including anti-inflammatory and analgesic effects… cannabis-based drugs have therapeutic potential in inflammatory diseases, including rheumatoid arthritis (RA) and multiple sclerosis (MS)…aim of this study was to determine whether the key elements of the endocannabinoid signalling system.. are expressed in the synovia of patients with osteoarthritis (OA) or RA… Our data predict that the cannabinoid receptor system present in the synovium may be an important therapeutic target for the treatment of pain and inflammation associated with OA and RA.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2453762/?tool=pubmed

Rheumatoid arthritis, cannabis based medicine eases pain and suppresses disease

“The first study to use a cannabis-based medicine (CBM) for treating rheumatoid arthritis has found that it has a significant effect on easing pain and on suppressing the disease”

http://www.medicalnewstoday.com/releases/33376.php

Cannabinoids suppress inflammatory and neuropathic pain by targeting α3 glycine receptors

TRUTH: “Cannabinoids suppress inflammatory and neuropathic pain by targeting α3 glycine receptors… nonpsychoactive cannabinoids can potentiate glycine receptors (GlyRs), an important target for nociceptive regulation at the spinal level… We report that systemic and intrathecal administration of cannabidiol (CBD), a major nonpsychoactive component of marijuana, and its modified derivatives significantly suppress chronic inflammatory and neuropathic pain without causing apparent analgesic tolerance… These cannabinoids may represent a novel class of therapeutic agents for the treatment of chronic pain and other diseases involving GlyR dysfunction.”

http://www.ncbi.nlm.nih.gov/pubmed/22585736